DESCRIPTION (Applicant's abstract): Many hundreds of studies of acute mountain sickness (AMS) over the past two centuries have examined the role of ventilation, pulmonary gas exchange and fluid balance, yet the pathophysiology of AMS remains largely unsolved. AMS incurs significant medical risks and costs since as many as 5 percent of cases can develop life-threatening high altitude cerebral edema (HACE). AMS itself is a substantial public health problem with a prevalence of 15-65 percent in visitors to high altitude. This proposal focuses on the role of brain swelling, which can include elevated brain water and blood volume, in the pathophysiology of AMS. This proposal uses exercise as a tool to develop more severe symptoms of AMS sooner than would be the case in resting subjects. Our approach departs from the traditional paradigm, followed by many of us in this field, of searching for clues to the pathophysiology of AMS in the observed peripheral responses (pulmonary, renal, vascular). Our rationale for focusing on brain swelling is that a) the symptoms of AMS are largely neurological; b) HACE, considered the end-stage of severe AMS, has recently been identified as a vasogenic edema, opening the door for a role for blood-brain barrier (BBB) permeability in AMS; c) new, noninvasive techniques make measurement of brain water and blood volume possible; and d) available experimental evidence and theoretical arguments support a significant role for brain swelling in the pathophysiology of AMS. We recently showed that exercise caused a more than 3 fold rise in AMS symptom severity, a drop in arterial oxygen saturation (SaO2) during exercise, and slight fluid retention. We also recently showed that subjects ill with AMS had a small drop in plasma volume and a large rise in extracellular water compared to those that remained free of AMS. In further studies, magnetic resonance imaging revealed that most brains swell when humans ascend to high altitude. Our overall hypothesis is that brain swelling causes the symptoms of AMS. Our approach is to apply several new and innovative technologies to solving the pathophysiology of AMS. These include noninvasive techniques to measure and manipulate cerebral blood volume, intracranial pressure, BBB opening, cerebrospinal volumes and selected cellular, molecular and genetic responses to hypoxia in people developing AMS. Our three specific aims are 1) to determine the role of elevated brain water in brain swelling and AMS; 2) to determine the role of BBB permeability in AMS; and 3) to determine the role of select cellular, molecular and genetic factors in AMS. The results from the proposed studies will increase our understanding of the role of the brain, brain water and brain swelling in other conditions, both those associated with oxygen depravation, and those where the primary insult is to the brain.